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Nat Genet. 2013 Oct;45(10):1190-7. doi: 10.1038/ng.2743. Epub 2013 Sep 1.

Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes.

Author information

1
1] Division of Infectious Disease, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA. [2] Center for Emerging and Re-emerging Pathogens, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA. [3] Department of Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.

Abstract

To study the evolution of drug resistance, we genetically and biochemically characterized Mycobacterium tuberculosis strains selected in vitro for ethambutol resistance. Mutations in decaprenylphosphoryl-β-D-arabinose (DPA) biosynthetic and utilization pathway genes Rv3806c, Rv3792, embB and embC accumulated to produce a wide range of ethambutol minimal inhibitory concentrations (MICs) that depended on mutation type and number. Rv3806c mutations increased DPA synthesis, causing MICs to double from 2 to 4 μg/ml in a wild-type background and to increase from 16 to 32 μg/ml in an embB codon 306 mutant background. Synonymous mutations in Rv3792 increased the expression of downstream embC, an ethambutol target, resulting in MICs of 8 μg/ml. Multistep selection was required for high-level resistance. Mutations in embC or very high embC expression were observed at the highest resistance level. In clinical isolates, Rv3806c mutations were associated with high-level resistance and had multiplicative effects with embB mutations on MICs. Ethambutol resistance is acquired through the acquisition of mutations that interact in complex ways to produce a range of MICs, from those falling below breakpoint values to ones representing high-level resistance.

PMID:
23995136
PMCID:
PMC6103293
DOI:
10.1038/ng.2743
[Indexed for MEDLINE]
Free PMC Article

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